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Risk factors such as maternal age, parity, previous siblings' death, inbreeding of parents, birth weight, birth length were examined in a population-based prospective study in four population groups at different levels of urbanization in and round Lahore, Pakistan. From September 1984 to March 1995, 2967 full-term, single born infants were followed from the 5th month of gestation to 12 months of age. Logistic regression analysis showed a significant relative risk (RR) of infant death associated with parents' consanguinity (RR = 1.8), birth weight (RR = 1.8) and elder siblings' death (RR = 1.7). The risk attributed to these factors was 28, 17 and 25%, respectively. The number of lethal equivalents per gamete is about one. The B/A ratio 10.36 suggests that the genetic load is likely to be mutational. In countries like Pakistan, where consanguinity is favourably practiced, a substantial proportion of infant deaths may be prevented by cessation of such marriages. The implications of this finding for the Pakistani community are discussed.

A large Swedish family with more than 250 cases of Best's macular dystrophy has been clinically and genetically studied. The gene was traced to a couple born in central Sweden in the 17th century. Highly significant evidence for genetic linkage to DNA markers on chromosome 11q13 was detected. A lod score of 15.12 was obtained at recombination fraction 0.01 with DNA marker INT2 (also called FGF3). The retinally expressed gene ROM1, which maps to the same chromosomal region is a candidate for this genetic disease.

Two patients with oro-facio-digital syndrome type II (OFD-II, Mohr syndrome) with associated cerebellar atrophy are described. Three other cases of the Mohr syndrome with cerebellar abnormalities are cited from the literature. Cerebellar involvement seems to be a clinical feature of this syndrome. Unfortunately, there is a lack of CNS reports for many of the previously described patients. In all cases with this entity, careful neurological and radiological examinations of the cerebellum are recommended.

Two families with the congenital X-linked infantile form of myotubular myopathy have been investigated by linkage analysis using markers from the X-chromosome. Linkage was found at the locus Xq28 (with DXS52). The analysis gave a peak lod score of 2.41 at the recombination fraction zero. Free recombinations (theta = 0.50) were seen using the markers DXS84, DXS14 and DXS146 from the p arm of the X-chromosome. Since the disorder is very rare, it is important to add cumulative linkage data from the few families that do exist.

In a Swedish multicenter study, 102 cases of infantile autism (I.A.) were examined for fragile X (q27). The fragile X syndrome was observed in 13 of the 83 (16%) boys with I.A., but in none of the 19 girls with I.A.

Catechol-O-methyltransferase (COMT) activity in erythrocytes was measured in six children with Down's syndrome and in their parents to determine if COMT activity is related to a gene on chromosome 21. A gene dosage effect was a possible explanation of the COMT value in three of the children but not in the other three.

The activity of platelet monoamine oxidase in Down's syndrome cases was significantly lower than that of controls. This difference was found for both males and females, and with tyramine, tryptamine and beta-phenethylamine as substrate. The Km values of the monoamine oxidase towards tryptamine as substrate from controls and Down's syndrome patients were similar.

A clinical study was performed on 14 patients with diastrophic dysplasia (DD), including three pairs of sibs. Six of these patients, including two pairs of sibs, died shortly after birth of respiratory and circulatory insufficiency. We consider these six patients to represent a special lethal variant of DD. In all infants with the lethal variant of DD the birth weight was lower than in those with the non-lethal variant. There were also roentgenological differences between these two groups. Overlapping in joints and dislocation of the cervical spine were seen in all the lethal cases. In addition, four of the six patients with lethal DD cases had a congenital heart defect, and none in the non-lethal group.

In a family with a balanced translocation t(8;19)(p21p13), there was a boy with true hermaphroditism and a karyotype 46,XX/46XY, t(8p;19p), and a woman with Turner mosaicism 46,XX, t(8p;19p). Both of them had whole body chimerism, which in the boy and possibly also in woman was due to the occurrence of double fertilization followed by fusion of the zygotes. The pathogenetic importance of the translocation for the development of these aberrations, and the clinical picture in the two patients are discussed.

Sjögren-Larsson syndrome (SLS), originally described in Sweden, has been studied in a countrywide survey. A total of 58 SLS patients in 41 families were traced, 35 of them still alive. Thirty patients, 23 alive and seven deceased, have not been reported earlier. The mean incidences per 100,000 in the years 1901-1977 were 0.6 in the whole of Sweden, 10.2 in the county of Västerbotten and 2.7 per 100,000 in the county of Norrbotten. In the above-mentioned areas, the prevalence figures of SLS on 31st December 1978 were estimated to be 0.4, 8.3 and 2.6 per 100,000 persons, the frequencies of SLS gene carriers 0.5, 2.0 and 1.0%, and the gene frequencies 0.002, 0.010 and 0.005, respectively. Of the 58 identified Swedish SLS patients, 45 were born in a restricted area in the northeast of Sweden.

Chromosomal analyses of cultured lymphocytes from nine patients with familial multiple endocrine adenomatosis (MEA) syndrome type I from six families and two patients - father and daughter - with familial MEA syndrome type II showed an increased frequency of chromosomal breakage. The frequency of sister chromatid exchanges was not increased.

In view of the different modes of inheritance and the different prognoses of the two oro-facio-digital syndromes, type 1 (OFD-I) and type 2 (OFD-II), it is important to establish a correct diagnosis in these patients. In this report two new patients with the OFD-I syndrome are presented. One of them (Case 1) had multiple congenital malformations and never made any mental contact. She died at the age of four months and autopsy of the brain revealed abnormalities typical of the syndrome, which are discussed. The other patient (Case 2) has so far had normal mental development. Although these two patients were affected to a very different degree, they both presented the clinical and radiological characteristics of the OFD-I syndrome. These two patients and previously reported cases of the OFD-I and OFD-II syndromes were compared with a patient with the OFD-II syndrome (Case 3), a patient reported earlier who is undergoing follow-up. The radiological features of the skeleton in the two syndromes are presented. The irregular mineralization of the hands and feet characteristic of OFD-I, but not of OFD-II, seems to offer a good opportunity to distinguish between these two syndromes. It is suggested that this finding is pathognomonic for the OFD-I syndrome.

A familial 13p;15q translocation was ascertained through a mentally retarded boy with a proximal trisomy 15 syndrome. His mother, who was a balanced 13p;15q carrier, had in addition a legal abortion after 22 weeks of gestation because of a prenatal diagnosis of distal trisomy 15 in a male foetus. Her mother and two sisters, who were balanced carriers, all had children with either a normal karyotype or a balanced translocation or had had pregnancies resulting in an early spontaneous abortion.

In populations in which a particular autosomal recessive disorder is treatable and relatively common, and for which there is a simple diagnostic test, newborns can be screened and treated. For some disorders, such as alpha 1-AT, young people can be screened and given appropriate advice to ameliorate the future symptoms. For some severe common and non-treatable autosomal recessive disorders, for example cystic fibrosis, carrier tests will probably soon be available for population screening of young people. Couples found to be carriers can then be offered prenatal diagnosis and termination of the pregnancy, if the fetus is affected. In the not-too-distant future the approaches will hopefully be treatment and correction of these disorders in the affected fetus or newborn.

Two brothers, the only children of healthy, unrelated parents with normal karyotypes, had 47,XXY-Klinefelter's syndrome and bilateral testicular teratomas. The oldest XXY-boy had, in addition, congenital hydrocephalus caused by congenital stenosis of the aqueduct of Sylvius.

The finger- and palm dermal-ridge patterns of all Swedish cases with the Sjögren-Larsson syndrome (SLS) were studied. The dermatoglyphic patterns of the SLS material showed variations from the normal material. This indicates an early prenatal pathological influence on the formation of dermatoglyphics in SLS.

Two young siblings with hereditary spastic diplegia and mental retardation (Böök's syndrome) have had detailed clinical investigations since infancy. The inheritance pattern of this syndrome in the present family fits well with an autosomal recessive trait--with affected sibs of opposite sex, born to consanguineous healthy parents.

X-linked mental retardation (MR) associated with a fragile X chromosome was found in two Swedish families. The fragile X chromosome was demonstrated in 5/5 boys with mental retardation. Clinical data on four of these boys are presented. In one of the families, the mental retardation was associated with macro-orchidism, large hands and large, folded ears. In the other family, macro-orchidism was not seen, possible because the boys were younger. Fragile site X chromosomes were also seen in three obligate carriers. A summary of earlier published cases of X-linked MR associated with the fragile X chromosome is given.

During a 4 1/2-year period a special study of 207 consecutive perinatal deaths, including clinical, genetical, roentgenological and autopsy investigations, was undertaken with the aim of identifying inherited malformations with a high risk of recurrence to subsequent sibs. Fifty-three of the children dying perinatally were malformed. In 13 cases the cause of the malformation was purely genetic; 11 were caused by mutant genes of large effect, and two by chromosomal aberrations. Information from such a study provides a good basis for genetic counselling of the family.

A case of duplication of segment p13-p15 of the short arm of chromosome 5 as the result of an insertional translocation in a mentally retarded girl with congenital anomalies is reported. Some of the apparently balanced carriers of the inverted insertion showed minor congenital anomalies.

Fragile-X mental retardation (FRAX-MR) is one of the more common X-linked disorders affecting 1 in 1,500 newborn males. This disease is characterized by the expression of fragile site in the region q27.3 of the X-chromosome of affected boys when their lymphocytes are cultured in folate deficient medium. In most patients there is macroorchidism postpubertally. The clinical diagnosis of carrier females based on the expression of fragile site in Xq27.3 is usually difficult and sometimes impossible. About half of the carrier females escape diagnosis by this method. Furthermore, prenatal diagnosis is not always feasible. Using Restriction Fragment Length Polymorphism (RFLP) and cloned DNA segments from the region Xq27-Xqter as probes, we have investigated Swedish families with FRAX-MR in three generations. Interesting observations, previously unreported to our knowledge, have been made in some patients and carrier mothers, using one of the probes which is localized to the distal end of Xq. The significance of these findings and the linkage of the disease locus to the different probes used in this study is presented.

Sixteen patients (13 males and 3 females) with minor neurodevelopmental disorders from 7 families were examined in an etiologic study. In four of the families (3, 5, 6 and 7) no brain damaging factors could be traced in the prenatal, perinatal or postnatal periods, and genetic main etiologies were strongly suspected. In one family (1) alcohol abuse during the pregnancies was thought to be an etiologically contributing factor. Potentially brain damaging factors were demonstrated in at least one patient from each of the remaining two families (2 and 4), and might, in these cases, have interacted with hereditary factors.

Two siblings with Zellweger's cerebro-hepato-renal syndrome are reported. The two children both had multiple anomalies associated with Zellweger's syndrome such as characteristic facial appearance, cerebral dysfunction, muscular hypotonia, liver abnormalities, failure to thrive, marasm and early death. One of the children, a girl, lacked several anomalies that were present in her brother. In one of the children bile acid analysis was performed by use of gas chromatography-mass spectrometry. 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid (THCA) and varanic acid, both precursors of cholic acid, were found. The defect bile acid synthesis may be due both to liver mitochondrial abnormalities and to the absence of liver peroxisomes, conditions known to occur in Zellweger's syndrome.

The optimality of prenatal and perinatal conditions, serum levels of radioreceptor-assayable somatomedins and activity of catechol-0-methyltransferase in erythrocytes were examined in 13 dysequilibrium (DES) patients. No differences from normal controls were found. As a group, the DES patients were not more exposed to non-optimal prenatal and perinatal events than healthy controls. No association between DES and somatomedin levels or between DES and catechol-0-methyltransferase activity was demonstrated.

Prenatal chromosome analysis revealed that a 34-year-old, gravida 2 mother was pregnant with a XXY foetus. She had previously given birth to a 21-trisomic boy with another spouse. Both parental karyotypes were normal, but a high frequency of associations between satellited chromosomes was observed in maternal lymphocytes. The possibility that increased satellite associations may predispose to aneuploidy in the offspring is discussed. The finding of normal testicular histology in the aborted XXY foetus provides evidence that the characteristic XXY testicular dysgenetic lesions are likely to occur not earlier than in the late prenatal period.

A mentally retarded boy with a ring chromosome 22, where most of band q13 was deleted, is reported. The fact that the leucocyte beta-galactosidase and alpha-galactosidase B activities were normal, but the arylsulphatase A activity only half of the normal is consistent with a gene dosage effect and that the arylsulphatase A locus is located more distally, than the gene loci for the other two enzymes, in the deleted part of 22q13.

The effect of folic acid intake on the frequency of fragile X positive cells and some behavioural characteristics were evaluated in 5 boys and 4 adult males with the fragile X syndrome. The expression of fragile X was nullified in 6 and decreased in 3 of the 9 patients. Behavioural and motor ability were considered to have improved in 4 of the 5 boys but not in the 4 adults with fragile X syndrome.

A follow-up investigation of 24 patients with hereditary spasticity in a geographically isolated northern Swedish population, first examined by Böök (1953), was performed. Fifteen of them were dead. During the period from 1950-1972 five new cases of spastic syndromes were diagnosed in this population. The patterns of clinical symptoms and the genetic associations between the new and 24 previously reported patients with spastic syndromes were analyzed. Three of the five new cases had a specific syndrome. This starts in the first years of life with ataxia, which is followed by dysarthria, spasticity and jerky intention tremor. Initially the patients are mentally normal, but there seems to be slight mental deterioration through the years. The disorder is a progressive spinocerebellar degeneration with autosomal recessive inheritance.

Twenty-six mentally retarded patients from a North Swedish geographically isolated population were studied. The mentally retarded patients were short with pycnic body type. Neurological and psychiatric stigmata of variating functions and degrees were recorded. Neurogenic hearing defects, impaired vision, pathological EEG, widened subarachnoidal space found in CT, were among these stigmata. In three patients a urinary substance, probably urocanyl-glycine, was found. The erythrocyte uroporphyrinogen-I-synthetase activity was high in four patients. Chromosome analysis showed some abnormalities which, however, were not systematically present. In the near family 23 persons with schizophrenia were found. The relationship between the mental retardation and the schizophrenic psychosis in the present families has not been explained. Further studies are called for to elucidate the genetic and environmental factors responsible for the two conditions.

In a family where the mother carried a fragile site at 17p12, RFLP-analysis with the X-specific probe L1.28 showed that the 46,XY/47,XXY mosaicism detected in her Klinefelter son was due to a non-disjunctional event in paternal meiosis I, followed by a secondary loss of an X-chromosome by a mitotic non-disjunction. Thus, an association between the primary meiotic non-disjunction and the presence of the fragile site could be excluded.

A girl, who was the product of the first recognized conception by healthy and chromosomally normal parents, and who was born 5 weeks before term with a birth weight of only 1,690 g, was found to have a ring-1 chromosome, r(1), in almost all cells analysed. A minor proportion of cells had a normal diploid chromosome complement including two regular No. 1 homologues. A few cells contained a large dicentric ring, and two monocentric ring-1 chromosomes were simultaneously observed in a few other cells. Q- and G- banding revealed the r(1) chromosome to be apparently non-deleted. The patient phenotypically resembled the three previously described human subjects with r(1) chromosomes, especially with respect to her remarkable growth failure and metal retardation. From consideration of data available on general development in subjects with an autosomal ring chromosome, it appears likely that the presence of such a ring chromosome per se in an early foetal chromosome complement may predispose to significantly retarded intrauterine and postnatal growth. Various genetical implications, including mitotic irregularities with subsequent loss of cells at division, are thought to account for the significant reduction of body mass in these patients.

The activity of gamma-glutamyl transferase (GGT) was measured in amniotic fluid collected between the 16th and 30th weeks of gestation from 81 pregnancies with fetuses affected by chromosomal aberrations, nine with different types of inborn errors of metabolism, two with hemophilia A and one with fragile X syndrome. The GGT activity was compared with that from 1000 normal pregnancies and deliveries resulting in healthy newborns. Contamination of amniotic fluid by blood did not affect the GGT activity. Pathologically decreased activity was found in 25 of 56 amniotic samples from pregnancies with fetal autosomal chromosomal aberrations (44.6%). It was decreased in 15 of 35 pregnancies with fetal trisomy 21 (43%), in 11 of 19 pregnancies with fetal trisomy 18 (58%), in one of three pregnancies with fetal trisomy 13 and in two pregnancies with fetal trisomy 8 and triploidy, respectively. In only three of 16 pregnancies with fetal sex chromosomal aberrations was the GGT activity low. Increased GGT activity was found in three of six pregnancies with unbalanced structurally rearranged karyotypes of the fetuses. Normal GGT activity was observed in all nine amniotic fluid samples from pregnancies with fetuses affected with different forms of inborn errors of metabolism diseases, in the two pregnancies with hemophilia A and in the pregnancy with a male fetus with fragile X syndrome. These and earlier findings indicate that the GGT activity in amniotic fluid is mostly decreased in pregnancies with severe fetal developmental abnormalities, such as autosomal chromosomal aberrations, which could possibly be secondary to an alteration of the microvillar transport system of GGT to the amniotic fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

The relations between some hereditary and environmental factors and the variation in infant birth weight were estimated by multiple linear regression analyses on a sample of 276 Scandinavian single term pregnancies. Gestational age explained 10.9%, fetal factors (maternal and paternal birth weights and fetal sex) 7.9%, maternal factors (parity, pre-pregnancy weight and height) 5.5% and external factors (adjusted weight gain and smoking) 5.8% of the variation in infant birth weight. It is concluded that maternal and paternal birth weights are rather poor predictors of infant birth weight. Together they explain only 5.6% of the variation in infant birth weight at term.

In an extensive etiological study of an unselected series of mildly mentally retarded children (MMR) (IQ 50-70) born 1959-1970 in a northern Swedish county, 5 of 110 boys (4.5%) and none of 61 girls had a fragile site on the distal end of the X-chromosome (Fra Xq 28). Consequently fragile X was seen in 2.9% of the total series of 171 children. In a combined series of severe and mild mental retardation, the incidence of the fragile X syndrome was calculated to be 1:3000 in the county of Västerbotten. Next to trisomy 21 the fragile X syndrome was the most common single identified cause of MMR in boys. A cytogenetic investigation using special cultural conditions and banding techniques should be performed in cases of mental retardation of unclear etiology and in possible female carriers.

X-chromosome-specific DNA probes were used to study a new type of muscular dystrophy (MD) presented by two boys in a family in which there was no previous history neuromuscular disease. Clinical investigations showed evidence of myogenic myopathyia, but its exact nature could not be established. The results of the DNA analysis exclude DMD, BMD and EMD. We suggest a probable autosomal recessive inheritance for the MD seen in this family.